Abstract
Purpose: To explore and identify cyclooxygenase (COX) inhibitors with optimal potency and efficacy using an arylpropionic acid class of drugs as lead molecules.Methods: The selected lead molecules were dimerised through chemical processes (reflux condensation) and characterised in terms of structural properties using infrared, proton nuclear magnetic resonance, electron impact mass spectrometry, and elemental analysis techniques. The molecules were evaluated pharmacologically for acute toxicity and anti-inflammatory (carrageenaninduced paw oedema test), analgesic (acetic acid-induced writhing test in mice), and antipyretic (Brewer’s yeast-induced pyrexia test in mice) activities against control (normal saline) and relevant reference standard drugs. Docking analyses were also performed to assess possible protein–ligand interactions.Results: The test compounds were non-toxic at doses of 50, 100 and 150 mg/kg body weight, ip. Pharmacological evaluation revealed that the test compounds, TC-I through TC-IV, had significant antiinflammatory and peripheral analgesic activities (p < 0.001). An antipyretic test showed that TC-I, -II, and -III showed highly significant antipyretic activities at all doses tested. TC-IV at 20 and 30 mg/kg body weight exhibited significant antipyretic activities (p < 0.05), while at 50 mg/kg body weight, the activity was highly significant (p < 0.001). Molecular modelling revealed strong inhibitory interactions with docking scores of 116.2, 128.8, 144.2, and 136.0 kcal/mol, respectively, in comparison with the reference ligand, flurbiprofen (94.9 kcal/mol).Conclusion: The dimerised lead drug molecules showed significant anti-inflammatory, analgesic, and antipyretic activities in animals and may further be explored as potential new drug candidates for inflammatory conditions.Keywords: Analgesic, Anti-inflammatory, Antipyretic, Arylpropionic acid, COX-2 inhibitors, Molecular docking
Highlights
Cyclooxygenase (COX) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), are commonly prescribed and used for their anti-inflammatory, analgesic, and antipyretic activities
Mice were distributed into five groups [groups I, II, III, IV, and V], n = 6 each; at levels of 10, 20, and 30 mg/kg body weight ip, doses of the test compounds were administered to the animals of the first three groups I–III, respectively
No acute toxicity was observed over the 24 h following dosing of 50, 100, or 150 mg/kg body weight of any test compound
Summary
Cyclooxygenase (COX) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), are commonly prescribed and used for their anti-inflammatory, analgesic, and antipyretic activities. The animals were observed for 6 h for any behavioural changes; mortality rates were determined at 24 h after administration of the test compounds [13] This test was performed on 30 mice distributed randomly into five groups, n = 6 each. Mice were distributed into five groups [groups I, II, III, IV (control), and V (reference standard)], n = 6 each; at levels of 10, 20, and 30 mg/kg body weight ip, doses of the test compounds were administered to the animals of the first three groups I–III, respectively. Twenty-four hours after the injection, changes in rectal temperature were recorded by inserting an oil-lubricated digital thermometer into their rectums at 1, 2, 3, 4, and 5 h Those mice whose rectal temperatures had increased by at least 0.3–0.5 °C were selected for further test procedures. Test compound (TC)-IV: mp: 185.5°C, Yield: 0.38 g, 79.5%: IR (KBr): max 3,145, 2,826, 1,806, 1,762, 1,624, 1,483, 1,414, 1,341, 939, 769 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 11.32 (s, 2H, NH), 7.44 (m, 12H, H-5/6/2 ́/3 ́/5 ́/6 ́), 7.25 (m, 4H, H-2/4 ́), 4.23 (q, 2H, CH), 1.53 (d, 6H, CH3); EI MS: m/z (relative abundance %): (M+, absent), 466 (3.9), 284 (100), 269 (63.6), 225 (27.7), 43 (43.4); elemental analysis for C30H26F2N2O2: C, 74.36; H, 5.41; N, 5.78; found: C, 74.28; H, 5.82; N, 5.84
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